Lipidome determinants of maximal lifespan in mammals

Abstract

Maximal lifespan of mammalian species, even if closely related, may differ more than 10-fold, however the nature of the mechanisms that determine this variability is unresolved. Here, we assess the relationship between maximal lifespan duration and concentrations of more than 20,000 lipid compounds, measured in 669 tissue samples from 6 tissues of 35 species representing three mammalian clades: primates, rodents and bats. We identify lipids associated with species’ longevity across the three clades, uncoupled from other parameters, such as basal metabolic rate, body size, or body temperature. These lipids clustered in specific lipid classes and pathways, and enzymes linked to them display signatures of greater stabilizing selection in long-living species, and cluster in functional groups related to signaling and protein-modification processes. These findings point towards the existence of defined molecular mechanisms underlying variation in maximal lifespan among mammals.

Molecular signatures of longevity: Insights from cross-species comparative studies

“…Several early studies quantified a number of biochemical and enzymatic parameters, revealing that the longer-lived species tend to have greater maintenance capacity, suffer less damage, and are more efficient at repair than the shorter-lived species (Holliday, 1997, 2006). However, until recently there had been very few cross-species comparative studies analyzing the entire mammalian transcriptome or metabolome (Bozek et al, 2017; Brawand et al, 2011; Fushan et al, 2015; Ma et al, 2015a; Ma et al, 2015b; Merkin et al, 2012). Besides the difficulty in obtaining reliable biological samples and the costs of large-scale omics studies, there are also some unique challenges in cross-species analyses that require particular attention.…”

“…In a recently published lipidome study, the levels of 13,000 to 21,000 hydrophobic compounds were quantified across 6 organs (brain cortex, cerebellum, heart, kidney, liver, and muscle) in 35 mammalian species belonging to rodents, primates, and bats (Bozek et al, 2017). Using logistic regression with elastic net penalty and adjusting for the confounding effects between lifespan and body mass, the authors constructed predictive models of the species’ maximum lifespans based on the lipid concentrations, with average prediction accuracy above 0.9.…”

“…The most consistent predictors of long lifespans included increased levels of triacylglycerols and decreased levels of glycerophospholipids and sphingolipids. The numbers of double bonds were also associated with lifespan variations, although the exact effects depended on the lipid classes (Bozek et al, 2017). Furthermore, genome analyses across these species revealed that the enzymes linked to these lipid classes and pathways displayed signatures of greater stabilizing selection among the long-lived species (Bozek et al, 2017), indicative of the concerted changes at both genomic and lipidomic levels in relation to the extended lifespans.…”

“…For example, a recently published study on hypoxia resistance in naked mole rat revealed the animal’s remarkable ability in utilizing fructose for glycolysis to avoid the lethal effects of oxygen deprivation (Park et al, 2017). In parallel, there are also a number of recent comparative studies on gene expression (Brawand et al, 2011; Fushan et al, 2015), splicing (Merkin et al, 2012), metabolites (Ma et al, 2015b), lipids (Bozek et al, 2017), and element levels (Ma et al, 2015a) across multiple mammalian species (Figure 2C), which start to reveal the molecular signatures associated with longevity (Table 2). Together, these studies provide the first insights into the general principles of lifespan control.…”

Evidence of evolutionary optimization of fatty acid length and unsaturation

“…In fact, the homeoviscous longevity adaptation hypothesis predicts a negative association between the degree of membrane fatty acid unsaturation and the longevity of organisms, which has received support in a comparative study of birds showing that longer lifespans correspond to species with longer fatty acids and higher proportions of MUFAs (traits that tend to be positively correlated; Galván et al ., ). An association between fatty acid unsaturation and longevity has also recently been reported in mammals (Bozek et al ., ). Consequently, it has been suggested that cell membrane has been an optimized feature during evolution (Pamplona, ; Naudí et al ., ), but this has never been tested.…”